Dermatological compositions

ABSTRACT

Compositions for enhancing the penetration of pharmacologically active agents through skin comprising a sugar ester in combination with a sulfoxide or phosphine oxide.

CROSS REFERENCE TO RELATED APPLICATION

This is a division, of application Ser. No. 647,943, filed Jan. 12,1976, now U.S. Pat. No. 4,046,886 which is a divisional of applicationSer. No. 541,902, filed Jan. 17, 1975, now U.S. Pat. No. 3,925,099 (Apr.20, 1976), which is a divisional of application Ser. No. 340,787, nowU.S. Pat. No. 3,896,238 (July 22, 1975), which is a continuation-in-partof Ser. No. 241,404, filed Apr. 5, 1972, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to compositions for topical application to animal(this term as used herein includes both humans and lower animals)tissue, said compositions providing enhanced penetration of variouspharmacologically active substances into or through such tissue.

The epidermal barrier to percutaneous absorption, i.e., the stratumcorneum, is a nearly impermeable heterogeneous animal tissue of whichkeratin is a major component. This tissue is found in animal skin andmucosal tissue such as tongue, gingiva, esophagus, and vagina. A widevariety of pharmacologically active substances are desirably appliedtopically to this epithelial tissue for an essentially local effectachieved upon penetration into or through the stratum corneum. Forexample, compositions used in the treatment of a variety of dermatoses,including acne vulgaris, tinea versicolor, acne rosacea and other skinmaladies associated with hyperplasia of the infected sebaceous gland,are desirably treated by topical medications. Likewise, eczema andeczema-like skin disorders caused by excessive cell proliferation aretreated by topical application of ointments and salves. Localizedinflammation which often accompanies arthritis and bursitis is treatedby topical medications, as is common muscular "strain" caused byoverexertion. Topical anesthetics are widely used in medicine anddentistry. The cosmetic efficacy of a variety of agents such asantiperspirants, rubifacients and emollients depends on the ability ofthe cosmetic agents to penetrate the epidermal barrier. Accordingly, itis seen that any means whereby the penetration of pharmacologicallyactive agents through skin can be enhanced is of substantial interest.

It is known that various surface-active compounds improve the activityof pharmacologically active substances, apparently by enhancing thepenetration of same through skin. For example, U.S. Pat. No. 3,326,768discloses that the presence of a phosphine oxide surfactant inantiperspirant compositions containing anticholinergic compounds appearsto increase activity by providing more efficient absorption of theactive agents at the site of application. U.S. Pat. No. 3,527,864discloses the use of alkyl sulfoxides to enhance the penetration of avariety of pharmacologically active agents through skin. The co-pendingapplication of Warren I. Lyness and James Scala entitled "Compositionsfor Topical Application to Animal Tissue and Method of EnhancingPenetration Thereby", Ser. No. 230,040, filed Feb. 28, 1972, relates tothe use of phosphine oxides to enhance the penetration of a variety ofagents through skin.

Many surface-active compounds enhance the permeability of skin byactually damaging the barrier tissue. Indeed, the degree of penetrationenhancement appears in some cases to be proportional to the extent oftissue damage. Certain organic solvents serve to enhance penetration ofsubstances through the epidermal barrier. For example, dimethylsulfoxide (DMSO) and homologous low molecular weight sulfoxides, whenused in solvent concentrations, e.g., 50% or more, will enhancepenetration of various substances; see U.S. Pat. No. 3,551,554. However,such compounds are systemically distributed in a very short time and cancause undesirable symptoms at these higher concentrations.

While the foregoing higher sulfoxides and phosphine oxides are suitablefor enhancing skin penetration, improved compositions providing agreater degree of penetration and improved clinical efficacy aredesirable. It is, therefore, an object of this invention to provideimproved compositions for topical application to animal tissue and animproved method for enhancing the penetration of pharmacologicallyactive substances through such tissue. It is a further object to providea method of enhancing the penetration of pharmacologically activesubstances into or through animal tissue, especially skin, withoutdamaging said tissue or causing adverse systemic effects. These andother objects are obtained herein as will be seen from the followingdisclosure.

SUMMARY OF THE INVENTION

The present invention encompasses compositions adapted to topicalapplication to animal tissue, said compositions providing enhancedpenetration of all manner of pharmacologically active agents throughsaid tissue. The tissue penetration enhancing compositions of thisinvention comprise: (1) at least about 0.1% by weight of a sugar esterof the type hereinafter disclosed; and (2) at least about 0.1% by weightof a compound selected from the group consisting of alkyl sulfoxides ofthe formula R¹ S(O)R² wherein R¹ is a straight chain or branched chainalkyl, alkenyl, substituted alkyl, heteroalkyl or hydroxy-substitutedalkyl substituent containing from 4 to 12 carbon atoms and R² is a lowmolecular weight (C₁ -C₈) alkyl or low molecular weight (C₁ -C₈)hydroxy-substituted alkyl substituent; and phosphine oxides of theformula R³ R⁴ R⁵ P(O) wherein R³ is an alkyl, aralkyl, substitutedalkyl, heteroalkyl, hydroxy-substituted alkyl substituent containingfrom 1 to 12 carbon atoms or aryl (e.g., phenyl, tolyl) containing 6 to9 carbon atoms, and R⁴ and R⁵ are each low molecular weight alkyl (C₁-C₄) or low molecular weight hydroxysubstituted alkyl (C₁ -C₄)substituents. Preferably, the compositions herein also contain apharmaceutically acceptable carrier. As will be seen hereinafter, thepharmaceutically acceptable carrier can be deleted from the formulationsin certain instances, e.g., when the low molecular weight liquidphosphine oxides are employed.

The above composition comprising the sugar ester and sulfoxide orphosphine oxide compound is applied to animal tissue in conjunction witha safe and effective amount of a pharmacologically active agent toenhance the penetration of said agent through animal tissue, especiallyskin, thereby providing a method aspect of the instant invention.

Of course, admixture of the skin penetration enhancing compositionhereinabove noted with the pharmacologically active agent provides apharmacologically active composition especially adapted to topicalapplication to skin. In general, such compositions comprise: (1) atleast about 0.1% by weight of a sugar ester; (2) a safe and effectiveamount (usually at least about 0.1% by weight) of a pharmacologicallyactive agent; and (3) at least about 0.1% by weight of a sulfoxide orphosphine oxide compound of the type disclosed above. Preferably, thesecompositions also contain a pharmaceutically acceptable carrier.

By the term "pharmacologically active agent" as used herein is meant anychemical material or compound suitable for topical administration whichinduces any desired local transitory effect on living structures (i.e.,animal tissue) contacted therewith (sometimes referred to as"penetrant"). Such substances include, for example, antimicrobials,including antibiotics, as well as antihistamines, local anesthetics,steroids, sunscreens, vitamins, elemental sulfur, various astringentmetal ions such as aluminum, iron, zirconium and zinc, which metal ionsprovide antiperspirants, anti-inflammatories, anti-metabolites,rubifacients and the like.

By the term "pharmaceutically acceptable carrier" as used herein ismeant any liquid, gel, solvent, liquid diluent, fluid ointment base,fluid suppository base and the like, which is suitable for use incontact with living animal tissue without any untoward physiologicalresponse and which does not interact with the other components of thecomposition in a deleterious manner and which can be used to establishthe compositions herein in their preferred liquid form.

The "enhanced penetration" effected through the use of the compositionsof this invention can be observed, for example, by measuring the rate ofdiffusion of the pharmacologically active substances through guinea pigskin using the diffusion cell apparatus, described in U.S. Pat. No.3,527,864.

DETAILED DESCRIPTION OF THE INVENTION

The compositions of this invention contain as an essential ingredient atleast about 0.1%, preferably about 0.1% to about 1.0% by weight, of asugar ester of the type hereinafter disclosed. While concentrationssubstantially greater than 1%, i.e., 50% and greater, of the said sugaresters can be present in such compositions, this represents an economicwaste inasmuch as the increased concentrations do not result in aconcomitant increase in the penetration enhancing properties of thecompositions.

The sugar esters suitable for use in this invention can be classified ashydrocarbyl and alkyl polyoxyalkylene esters of cyclic polyhydroxysaccharides wherein one or more of the hydroxyl groups on the saccharidemoiety is substituted with an acyl or polyoxyalkylene group. Hydrocarbylsugar esters can be prepared in well-known fashion by heating an acid oracid halide with a sugar, i.e., by a simple esterification reaction.When an acid halide is used to prepare the sugar esters it is preferableto have an organic base, e.g., pyridine, morpholine, and the like,present in the reaction system. The reaction proceeds to form the sugarester and the base hydrohalide. Acid chlorides, bromides and iodides aresuitable for preparing the sugar esters used herein; the acid chloridesare preferred. In an alternate procedure, a lower alkyl ester of thecarboxylic acid is heated with the sugar to form the sugar ester and alower alcohol. When this process is used, the ethyl, methyl and propylesters of the carboxylic acid can be employed.

The sugars employed in the preparation of the sugar esters used in theinstant compositions include monosaccharides, di-saccharides andoligo-saccharides wellknown in the art. As examples of the various kindsof sugars useful in the preparation of the sugar esters herein there maybe mentioned the dextrorotatory and levorotatory forms of glucose,fructose, mannose, galactose, arabinose and xylose. Typicaldi-saccharides include maltose, cellibiose, lactose, and trehalose.Typical tri-saccharides include raffinose and gentianose. Thedi-saccharides are preferred for use in the preparation of the sugaresters used in the compositions of this invention. Sucrose is especiallypreferred for this purpose.

Sucrose is typical of the di-saccharides used to prepare the sugaresters employed herein and has the formula: ##STR1## Sucrose can beesterified at one or more of its eight hydroxyl groups in thehereinabove described manner to provide the sucrose esters usefulherein. When sucrose is combined with an esterification agent in a 1:1mole ratio, sucrose monoesters are formed; when the ratio ofesterification agent to sucrose is 2:1, or greater, the di-, tri-, etc.,esters are formed, up to a maximum of the octa-ester. A similarsituation obtains in the preparation of sugar esters using the othersugars noted above.

Preferred sugar esters herein are those prepared by the esterificationof sugars at a mole ratio of esterification agent:sugar of 1:1 and 2:1,i.e., the mono-acyl and di-acyl sugar esters. Especially preferred arethe monoacyl and di-acyl sugar esters wherein the acyl substituentscontain from about 8 to about 20 carbon atoms. Of the mono-acyl anddi-acyl sugar esters, the respective esters of di-saccharide sugars,especially sucrose, wherein the acyl groups contain from about 8 toabout 20 carbon atoms are especially preferred. Sucrose monooleate hasbeen found to be particularly efficacious in the compositions herein.

Sucrose monooleate, the preferred sugar ester in the compositions ofthis invention, can be prepared by admixing sucrose and oleic acidchloride at a 1:1 mole ratio at a temperature of about 80° C. withsimple removal of the hydrogen chloride formed and recovery of sucrosemonooleate. Similarly, sucrose monooleate can be obtained by heating a1:1 mole mixture of methyl oleate and sucrose at a temperature of about90° C. in the presence of a base catalyst, distilling the methanolformed and recovering the sucrose monooleate. While it is not importantfor the purposes of this invention, the sucrose monooleate formed in theforegoing manner is believed to be esterified predominantly at thehydroxyl group labeled (1) in the above formula. However, commercialgrades of this material include, as minor components, compounds whereinthe sucrose is esterified at hydroxyl groups (2) and (3) as well as evensmaller amounts esterified at one or more of the other five ringhydroxyl groups. A similar situation obtains with the other sugar estersused herein. For example, raffinose, which can be considered to be acondensate of galactose and sucrose, can be esterified in the foregoingmanner in any one of the ten hydroxyl groups and used herein. However,it is believed that the esterification of raffinose occurs predominantlyat the --CH₂ OH group on the galactose ring, with minor amounts ofesterification also occurring at the --CH₂ OH groups on the sucroseportion of the molecule. Accordingly, when esterified raffinose is usedas a sugar ester herein, it comprises a mixture of these various esters.Such sugar esters mixtures are entirely suitable for use herein.

The following is a list of typical sugar esters suitable for use in theinstant invention but is not intended to be limiting of such esters andis only mentioned by way of exemplification: glucose monooctanoate,glucose monocaprate, glucose monolaurate, glucose monomyristate,galactose monopalmitate, galactose monostearate, galactose monooleate,mannose mono-eicosanate, glucose dicaprate, glucose dilaurate, glucosedioleate, galactose dimyristate, galactose dioleate, mannosedipalmitate, xylose dioleate, xylose dioctanoate, xylose di-eicosanate,sucrose monooctanoate, sucrose monocaprate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosemonooleate, sucrose mono-eicosanate, sucrose dioctanoate, sucrosedicaprate, sucrose dilaurate, sucrose dimyristate, sucrose dipalmitate,sucrose distearate, sucrose dioleate, sucrose di-eicosanate, sucrosetrioctanoate, sucrose tricaprate, sucrose trilaurate, sucrosetrimyristate, sucrose tripalmitate, sucrose tristearate, sucrosetrioleate, sucrose tri-eicosanate, maltose monooctanoate, maltosemonocaprate, maltose monolaurate, maltose monomyristate, maltosemonopalmitate, maltose monostearate, maltose monooleate, maltosemono-eicosanate, maltose dioctanoate, maltose dilaurate, maltosedioleate, cellibiose distearate, cellibiose dioleate, cellibiosedi-eicosanate, galactose monooctanoate, galactose monocaprate, galactosemonolaurate, galactose monomyristate, galactose monopalmitate, galactosemonostearate, galactose monooleate, galactose monoeicosanate, galactosedioctanoate, galactose dilaurate, galactose dimyristate, galactosedipalmitate, galactose distearate, galactose dioleate, galactosedi-eicosanate, galactose trioctanoate, galactose trioleate, cellibiosetricaproate, cellibiose trilaurate, cellibiose trioleate, maltosetristearate, maltose trioleate, maltose tri-eicosanate, raffinosemonooctanoate, raffinose monocaprate, raffinose monolaurate, raffinosemonomyristate, raffinose monopalmitate, raffinose monostearate,raffinose monooleate, raffinose mono-eicosanate, raffinose dioctanoate,raffinose dioleate, raffinose trioleate, gentianose octanoate,gentianose monostearate, gentianose monooleate, gentianosemono-eicosanate, gentianose dioctanoate, gentianose dilaurate,gentianose dioleate, gentianose di-elcosanate, gentianose tricaprate,gentianose trilaurate and gentianose trioleate. Preferred sugar estersherein are sucrose monooctanoate, sucrose monodecanoate, sucrosemonolaurate, sucrose monomyristate, sucrose monopalmitate, sucrosemonostearate, sucrose monooleate and sucrose dioleate.

Other sugar esters suitable for use in the compositions of thisinvention are the alkyl polyoxyalkylene sugar esters wherein onehydroxyl group is substituted with a C₈ -C₁₈ alkyl group and wherein oneor more of the hydroxyl groups on the sugar molecule are replaced by anester or ether substituent containing the moiety (CH₂)_(x) -O_(y)wherein x is an integer from 2 to about 4, preferably 2, and wherein yis an integer from about 1 to about 50, preferably 8 to 30, i.e.,polyoxyalkylene substituents. Especially preferred herein are sugaresters wherein the polyoxyalkylene substituent is a polyoxyethylenesubstituent containing from about 8 to about 30 polyoxyethylene groups.Such materials wherein sorbitan is the sugar moiety are commerciallyavailable under the tradename "Tweens". Such mixed esters can beprepared by first acylating a sugar at a 1:1 mole ratio with ahydrocarbyl acid halide followed by reaction with the correspondingpolyoxyalkylene acid halide or alkylene oxide to provide the desiredmaterial. The simple polyoxyalkylene esters of disaccharides, especiallysucrose, wherein the polyoxyalkylene groups contain up to about 20alkylene oxide moieties are another useful class of sugar esters herein.It is to be understood that the polyoxyalkylene derivatives of any ofthe sugars noted hereinabove are suitable for use as the sugar estersherein. The following list of typical polyoxyalkylene sugar derivativesand mixed polyoxyalkylene-acyl sugar esters suitable for use as thesugar ester component in the instant invention is not intended to belimiting of such esters and is mentioned by way of exemplification. Thenumeral following the polyoxyalkylene substituent denotes the number ofrepeating oxyalkylene groups in the polymer chain and is standardterminology for these kinds of materials. Suitable polyoxyalkylene sugaresters include sucrose monooleate polyoxyethylene (20); sucrosedipolyoxyethylene (30); fructose monopalmitate polyoxypropylene (10);galactose tri-polyoxybutylene (50); sucrose di-polyoxypropylene (15);sucrose monoeicosanate polyoxyethylene (20); sucrose dioleatepolyoxyethylene (20); sorbitan monooleate polyoxyethylene (20); sorbitanmonopalmitate polyoxyethylene (20); glucose monooctanoatedi-ethyleneoxide (1); glucose dioleate polyoxybutylene (20). Of theforegoing sugar esters, the sucrose monooleate polyoxyethylenes,especially the polyoxyethylene 10's, and the sorbitan monooleatepolyoxyethylenes, especially the polyoxyethylene 10's, are preferred inthe compositions herein.

The compositions herein also contain as an essential ingredient acompound selected from the group consisting of sulfoxides of the formulaR¹ S(O)R², wherein R¹ and R² are as defined hereinabove, and tertiaryphosphine oxides of the formula R³ R⁴ R⁵ P(O) wherein R³, R⁴ and R⁵ areas defined hereinabove. Preferred herein are the alkyl sulfoxideswherein R is an alkyl or hydroxyalkyl substituent containing about 8 toabout 12 carbon atoms and R² is a low molecular weight alkyl or lowmolecular weight hydroxyalkyl group containing about 1 to about 8 carbonatoms. Alkyl tertiary phosphine oxides wherein R³ is an alkyl orhydroxyalkyl substituent containing 8 to 12 carbon atoms and R⁴ and R⁵are each lower alkyl or lower hydroxyalkyl substituents are thepreferred phosphine oxides herein.

Examples of lower alkyl and lower hydroxyalkyl substituents in theforegoing sulfoxide and phosphine oxides include, for example, methyl,ethyl, propyl, hydroxymethyl, 1-hydroxypropyl, etc. Substituted alkylgroups referred to in the sulfoxide and phosphine oxide definitionsherein include alkoxyalkyl (e.g., methoxy) and ketoalkyl, for example;heteroalkyl groups include oxaalkyl, thiaalkyl, and azaalkyl, forexample.

The alkyl sulfoxides suitable for use herein include those materialsdisclosed in U.S. Pat. No. 3,527,864 and U.S. Pat. No. 3,551,554,incorporated herein by reference. The most preferred alkyl sulfoxidesfor use herein have group R¹ as a hydroxycarbyl alkyl or hydroxyalkylsubstituent containing from about 8 to about 12 carbon atoms, and R² asa low molecular weight hydrocarbyl alkyl substituent. If group R¹ of thealkyl sulfoxide contains less than about 8 carbon atoms, substantiallyhigher concentrations than the 10% concentration specified herein mustbe employed to enhance penetration. For example, hexyl methyl sulfoxidemust be used at a concentration of about 30% or more to significantlyenhance penetration. The lower homologues must be used at solventconcentrations, e.g., 50% or more to accomplish this purpose. At theseconcentrations these lower sulfoxides (below C₈) can produce undesiredsystemic effects in some individuals. If R¹ contains substantially morethan 12 carbon atoms, the sulfoxide will not be soluble enough toprovide the desired degree of penetration enhancement.

Examples of R¹ suitable herein include octyl, nonyl, decyl, undecyl,dodecyl, 3-decenyl, 2-dodecenyl, 3-undecenyl, 3-octenyl, 2-ketooctyl,2-ketodecyl, 2-ketoundecyl, 2-ketododecyl, 2-hydroxyoctyl,2-hydroxydecyl, 2-hydroxyundecyl, 2-hydroxydodecyl, 3-hydroxyundecyl,3-methoxyundecyl, 2-methoxydodecyl, 3,6-dioxadodecyl, 2-ethylhexyl, andbranched chain nonyl and dodecyl resulting from polymerization of threeand four moles of propylene, respectively. Examples of R² as lower alkylinclude methyl, ethyl, propyl, butyl, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, and 4-hydroxybutyl.

Especially preferred sulfoxides for the purposes of this invention arethe dialkyl sulfoxides wherein R¹ is a hydrocarbyl alkyl orhydroxy-substituted alkyl group containing from 8 to 12 carbon atoms andR² is methyl, ethyl or propyl. As examples of these preferred sulfoxidesthere may be mentioned octyl methyl sulfoxide, nonyl methyl sulfoxide,decyl methyl sulfoxide, undecyl methyl sulfoxide, dodecyl methylsulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxyundecyl methylsulfoxide and 2-hydroxydodecyl methyl sulfoxide. Decyl methyl sulfoxideis especially preferred.

The sulfoxide compounds disclosed herein can be used singly or incombination for the purpose of this invention. These compounds arereadily obtainable by well known methods. For example, they can beprepared by the conventional method of first preparing the correspondingthioether and then oxidizing to the sulfoxide. The methods of carryingout these steps are reported in A. Schoberl and A. Wagner "MethodenOrganischen Chemie", Houben-Weyl, 4th ed., Georg Thieme Verlog,Stuttgart, vol. IX, pp. 97-143, 211-218 (1955). Further methods forpreparing sulfoxide compounds are disclosed in U.S. Pat. Nos. 3,288,858;3,288,859; and 3,288,860, incorporated herein by reference.

The concentration of sulfoxide employed herein is at least about 0.1% byweight of the composition and can range from about 0.1% to about 10.0%by weight. If concentrations less than about 0.1% are used the degree ofpenetration enhancement attained, especially with the lower chain lengthsulfoxides (e.g., octyl methyl sulfoxide), is not appreciable. Ifconcentrations greater than about 10.0% are employed, solubilityproblems may be encountered with the higher chain length sulfoxides(e.g., dodecyl isopropyl sulfoxide) and no substantial improvement inpenetration is seen. Preferably, the concentration of sulfoxide willrange from about 0.1% to about 1% by weight of the total composition.

As disclosed hereinabove, the tertiary phosphine oxides useful in thecompositions of this invention are of the formula R³ R⁴ R⁵ PO. Examplesof R³ include methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, 2-propenyl, 3-decenyl, 2-dodecenyl,3-undecenyl, 3-octenyl, 2-ketobutyl, 2-ketohexyl, 2-ketooctyl,2-detodecyl, 2-ketoundecyl, 2-ketododecyl, 2-hydroxypropyl,2-hydroxyhexyl, 3-hydroxyheptyl, 2-hydroxyoctyl, 2-hydroxydecyl,2-hydroxyundecyl, 2-hydroxydodecyl, 3-hydroxyundecyl, 2-methoxybutyl,3-methoxyundecyl, 2-methoxydodecyl, 2-chlorodecyl, 3-chlorobutyl,2-thiomethylhexyl, 3,6-dioxadodecyl, 2-oxaheptyl, 3-azahexyl,2-thiadecyl, 2-ethylhexyl, phenyl, naphthyl, m-tolyl, benzyl, andbranched chain nonyl and dodecyl resulting from polymerization of threeand four moles of propylene, respectively. If the R³ group contains morethan about 12 carbon atoms, it has been found that enhanced penetrationdoes not occur.

Examples of R⁴ and R⁵ include methyl, ethyl, propyl, hydroxymethyl,1-hydroxypropyl, 2-hydroxyethyl, and the like.

Especially preferred phosphine oxides for the purpose of this inventionare those in which R³ is a hydrocarbyl alkyl or hydroxy-substitutedalkyl substituent containing from 8 to 12 carbon atoms and R⁴ and R⁵ areeach methyl, ethyl or propyl. As examples of these preferred phosphineoxides there may be mentioned octyl dimethyl phosphine oxide, nonyldiethyl phosphine oxide, decyl dimethyl phosphine oxide, undecyldimethyl phosphine oxide, dodecyl dimethyl phosphine oxide,2-hydroxydecyl dimethyl phosphine oxide, 2-hydroxyundecyl dimethylphosphine oxide and 2-hydroxydodecyl dimethyl phosphine oxide. Dodecyldimethyl phosphine oxide is especially preferred.

The foregoing phosphine oxides can be used singly, in combination, or incombination with the foregoing sulfoxides, for the purpose of thisinvention. These compounds can be prepared by methods disclosed by D.Karrell Berlin and George B. Butler, "Chemical Reviews" 60 243-259(1960). In general, the phosphine oxides are prepared by oxidizing thecorresponding tertiary phosphine for example, with hydrogen peroxide.Further methods for preparing phosphine oxides suitable for use hereinare disclosed in British Pat. Nos. 976,974 and 995,260, incorporatedherein by reference.

The desired concentration of phosphine oxide employed herein dependslargely on the chain length of R³ and the type of composition involved,but preferably ranges from about 0.1% to about 10% by weight. Ifconcentrations less than about 0.1% are used, the degree of penetrationenhancement attained, especially with the lower chain length tertiaryphosphine oxides (e.g., trimethyl phosphine oxide), is not appreciable.If concentrations of the higher chain length phosphine oxides (e.g.,dodecyl diethyl phosphine oxide) greater than about 10% are employed,solubility problems may be encountered and no substantial improvement isseen using such higher concentrations. Preferably, the concentration ofphosphine oxide containing an R³ group having from 8 to 12 carbon atomswill range from about 1% to 8% by weight of the total composition. Thesuitable concentrations for the lower molecular weight phosphine oxides,e.g., wherein R³ contains less than about 6 carbon atoms is from about10% to 90% and preferably above 50%, e.g., solvent concentrations.

The compositions comprising the sugar ester and skin penetrationenhancing agent disclosed herein are designed primarily for topicalapplication to tissue and are preferably in a liquid or semi-liquidstate. Accordingly, when solid sugar esters and/or sulfoxides orphosphine oxides are used to prepare the compositions herein, they arepreferably formulated in combination with a pharmaceutically acceptableliquid carrier. It is desirable that the selected liquid carrier becapable of co-dissolving the sugar ester and sulfoxide or phosphineoxide. When a pharmacologically active agent is incorporated in thecomposition in the manner hereinafter detailed, it is desirable that thetotal composition be capable of co-dissolving this component.

Carrier materials suitable for use in the instant compositions includethose well-known for use in the cosmetic and medical arts as bases forointments, lotions, salves, aerosols, suppositories and the like.Suitable carriers include, for example, water, liquid alcohols, liquidglycols, liquid polyalkylene glycols, liquid esters, liquid amides,liquid protein hydrolysates, liquid alkylated protein hydrolysates,liquid lanclin and lanolin derivatives, and like materials commonlyemployed in cosmetic and medicinal compositions. Exemplary carriersherein include alcohols, including both monohydric and polyhydricalcohols, e.g., ethanol, isopropanol, glycerol, sorbitol,2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol,mannitol, and propylene glycol; ethers such as diethyl or dipropylether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxeshaving molecular weight ranging from 200 to 20,000); polyoxyethyleneglycerols, polyoxyethylene sorbitols, and stearoyl diacetin.Oil-in-water emulsions such as cold cream bases can also be used.

Preferably, the carrier herein is a pharmaceutically acceptable liquidalcohol containing from about 2 to about 6 carbon atoms. Mixturescomprising from about 0% to 80% by weight of water and about 20% to 100%by weight of said C₂ to C₆ alcohols are also suitable. Suitable alcoholsherein include ethanol, isopropanol, hexanol, and the like. Especiallypreferred carriers herein are water-ethanol (ethyl alcohol) mixtures ata weight ratio range of about 1:20 to 5:1. Ethanol containing from about5% to about 50% by weight of water, especially 40:60 volume (i.e.,33.35% by weight) ethanol-water, is preferred as the carrier.

The compositions herein can also include various agents and ingredientscommonly employed in dermatological and cosmetic ointments and lotions.For example, perfumes, thickening agents such as carboxymethylcellulose,coloring agents and the like can be present in the compositions toprovide a more pleasing aesthetic aspect.

The following examples are intended to illustrate typical tissuepenetration enhancing compositions of this invention but are notintended to be limiting thereof. All materials used in the compositionsare commercially available, or can be prepared in the manner describedhereinabove. The enhanced tissue penetration of the variouspharmacologically active agents afforded by the compositions herein ismeasured by the techniques fully described in U.S. Pat. No. 3,527,864.Fluorescence microscopy of excised tissue is conveniently used toestimate tetracycline penetration.

EXAMPLE I

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    0.125                                                   Decyl methyl sulfoxide                                                                              0.125                                                   Ethanol               33.35                                                   Water                 Balance                                                 ______________________________________                                    

The above ingredients are blended mechanically and provide a fluidointment base adapted to topical application to skin and suitable forenhancing the penetration of all manner of pharmacologically activeagents into and through animal tissue. For example, tetracyclinehydrochloride (ca. 0.5%) is dissolved in the composition and is found topenetrate into animal skin to a substantially greater depth than whensimilarly applied in conjunction with ethanol-water, ethanol-water-decylmethyl sulfoxide, or ethanol-water-sucrose monooleate ointment bases.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of octyl methyl sulfoxide, nonyl methyl sulfoxide,undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxyundecyl methyl sulfoxide, and2-hydroxydodecyl methyl sulfoxide, respectively, and equivalent resultsare secured.

In the above composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monolaurate, sucrose monomyristate, sucrosemonopalmitate, sucrose monostearate, sucrose dipalmitate, sucrosedioleate, and sucrose monooleate polyoxyethylene (20), respectively, andequivalent results are secured.

EXAMPLE II

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate     1.0                                                    Dodecyl dimethyl phosphine oxide                                                                    10.0                                                    Isopropanol           75.0                                                    Water                 Balance                                                 ______________________________________                                    

The above ingredients are blended and provide a fluid ointment basesuitable for enhancing the penetration of all manner ofpharmacologically active agents into and through animal tissue. Forexample, tetracycline hydrochloride (ca. 0.5%) is dissolved in thecomposition and is found to penetrate into animal skin to a depthsubstantially greater than when similarly applied in conjunction withisopropanol-water, isopropanol-water-dodecyl dimethyl phosphine oxide orisopropanol-water-sucrose monooleate ointment bases.

In the above composition, the dodecyl dimethyl phosphine oxide isreplaced by an equivalent amount of octyl dimethyl phosphine oxide,nonyl dimethyl phosphine oxide, decyl dimethyl phosphine oxide, undecyldimethyl phosphine oxide, 2-hydroxydecyl dimethyl phosphine oxide,2-hydroxyundecyl dimethyl phosphine oxide, and 2-hydroxydodecyl dimethylphosphine oxide, respectively, and equivalent results are secured.

In the above composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monolaurate, sucrose monomyristate, sucrosemonopalmitate, sucrose monostearate, sucrose dipalmitate, sucrosedioleate, and sucrose monooctanoate, and sucrose monodecanoate,respectively, and equivalent results are secured.

EXAMPLE III

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    0.1                                                     Decyl methyl sulfoxide                                                                              0.25                                                    Carboxymethylcellulose                                                                              1.0                                                     Glycerol              15.0                                                    Ethanol               50.0                                                    Water                 Balance                                                 ______________________________________                                    

The above composition provides a creamy ointment base adapted to topicalapplication to skin and is suitable for enhancing the penetration of allmanner of pharmacologically active agents into and through animaltissue. For example, triamcinolone acetonide (ca. 0.1%) is dissolved inthe composition and is found to penetrate into animal skin to asubstantially greater depth than when similarly applied in conjunctionwith ethanol-water, ethanol-water-glycerol, ethanol-water-glycerol-decylmethyl sulfoxide, or ethanol-water-glycerol-sucrose monooleate creambases.

In the above composition, the ethanol is replaced by an equivalentamount of isopropanol and 1-hexanol, respectively, with equivalentresults.

A tacky, substantially anhydrous composition is prepared by deleting thewater and ethanol in the composition of Example III. The resulting tackycomposition is adapted to application to animal skin and is especiallysuited for use when removal of the composition by perspiration isdesirably avoided. The anhydrous composition promotes the penetration ofall manner of pharmacologically active agents into and through the skin.

From the foregoing, it is seen that the compositions herein areespecially adapted to topical application to animal tissue to enhancethe penetration of various pharmacologically active agents. In general,preferred compositions for this purpose comprise from about 0.1% toabout 1.0% by weight of sucrose monooleate from about 0.1% to about 1%by weight of decyl methyl sulfoxide from about 20% to about 70% byweight of water and from about 20% to about 70% by weight of ethylalcohol. The following is intended to illustrate the broad range ofpharmacologically active agents which can be employed in conjunctionwith the foregoing compositions and to illustrate that such compositionspromote the penetration of a wide variety of pharmacologically activeagents into and through animal tissue.

One class of pharmacologically active agents suitable for use inconjunction with the tissue penetration compositions herein are theantimicrobials. As used herein, the term "antimicrobials" includes boththe antibiotics such as the penicillins, tetracyclines, aureomycins,streptomycins, and griseofulvins, as well as the synthetically producedantimicrobial agents such as the phenols, the various chlorinatedphenolics, chlorinated aromatics and carbanilides, quaternary ammoniumcompounds, bis-biguanides and the like. Preferably, the antimicrobialagents used herein are soluble in the tissue penetration composition.Since the compositions herein usually contain a proportion of water,alcohol, or water-alcohol mixtures, as hereinabove described, theantimicrobial agents can be those which are soluble in water, alcohol,or water-alcohol mixtures.

Exemplary antimicrobial agents suitable for use herein include thetetracyclines as well as the salts thereof, for example, tetracyclinehydrochloride and the tetracycline phosphate complex marketed under thetrademarks "Tetrex" and "Panmycin Phosphate", and the like. Tetracyclineanalogs, e.g., the oxytetracyclines or terramycins, e.g., terramycinhydrochloride, terramycin disodium salt dihydrate, and the like are alsosuitable herein. The gramicidins, including gramicidin D and gramicidinS, can be used as the antimicrobial agent herein. Aureothricin,aureomycin, tyrothricin, and any of the penicillins, e.g., penicillinAT, penicillin BT, penicillin S potassium, penicillin V, and the like,are also useful as the antimicrobial agent. From the foregoing, it canbe seen that a wide variety of naturally-occurring antibiotic substancescan be employed as the penetrant in the instant compositions. In eachinstance, the compositions herein enhance the penetration of theforegoing antimicrobial agents into and through animal tissue.

Other suitable antimicrobial agents herein include thesynthetically-produced organic compounds recognized as havingantimicrobial properties. For example, the well-known quaternaryammonium salts, e.g., cetylpyridinium chloride, dodecyltrimethylammoniumbromide, decylmorpholinium sulfate, and the like, are suitable for useas the antimicrobial agent herein. Likewise, halogenated antibacterialagents such as 3,5,4'-tribromosalicylanilide,bis-(3,5,6-trichloro-2-hydroxyphenyl)methane,bis-(3,5-dichloro-2-hydroxyphenyl)sulfide,3-trifluoromethyl-4,4'-dichlorocarbanilide, and mixtures thereof, can beused in conjunction with the compositions herein to enhance theirpenetration into and through animal tissue. Another class ofantimicrobial agents are the well-known alkyl or aryl bis-biguanidecompounds. Such materials are commercially available. Also suitableherein are the salts, e.g., acetate, gluconate, hydrochloride, etc., ofthe foregoing bis-biguanides. Exemplary bis-biguanides suitable for useherein are 1,1'-hexamethylenebis[5'-(p-chlorophenyl)]-biguanide and theacetate and gluconate salts thereof, and1,1'-hexamethylenebis[5-(2-ethylhexyl)]-biguanide and the acetate andgluconate salts thereof. A number of other suitable syntheticanti-bacterial agents are described in U.S. Pat. No. 3,281,366 to Judge,et al., incorporated herein by reference.

Preferred antimicrobial agents for use herein include tetracycline,tetracycline hydrochloride, equilibrium mixtures of epi-tetracyclinehydrochloride and tetracycline hydrochloride (formed on dissolution oftetracycline hydrochloride in water), 3,5,4'-tribromosalicylanilide,bis-(3,5,6-trichloro-2-hydroxyphenyl)-methane,bis-(3,5-dichloro-2-hydroxyphenyl)sulfide,3-trifluoromethyl-4,4'-dichlorocarbanilide,1,1'-hexamethylenebis[5'-(p-chlorophenyl)biguanide,1,1'-hexamethylenebis[5'-(2-ethylhexyl)]biguanide, cetylpyridiniumchloride, zinc undecylenate, oxytetracycline, terramycin, gramicidin,aureomycin, neomycin, tyrothricin, sulfonilamide, penicillin and zincpyridinethione-1-oxide. Especially preferred antimicrobial agents hereininclude tetracycline hydrochloride and the equilibrium mixture oftetracycline hydrochloride and epi-tetracycline hydrochloride whichforms spontaneously after aqueous solutions of tetracyclinehydrochloride have been allowed to age at about 90° F. for about 28days. In general, this equilibrium mixture comprises about 40%-45% (wt.)tetracycline hydrochloride and 55%-60% (wt.) epi-tetracyclinehydrochloride.

The following examples are intended to illustrate the tissue penetrationenhancing compositions of this invention containing as thepharmacologically active component from about 0.005% to about 10% byweight of an antimicrobial agent.

EXAMPLE IV

    ______________________________________                                                               Percent                                                Ingredient             (By Weight)                                            ______________________________________                                        Sucrose monooleate     0.125                                                  Tetracycline hydrochloride                                                                           0.5                                                    Decyl methyl sulfoxide 0.125                                                  Ethanol                33.35                                                  Water                  Balance                                                ______________________________________                                    

The above composition is applied to animal skin and results in asubstantial increase in the depth of penetration of the tetracyclinehydrochloride over similar compositions without the sucrose monooleate.

The above composition is spread onto human skin affected with acne twicedaily for about two weeks (28 total applications; about 2 oz. totalproduct used). The treatment results in a substantial remission of acnelesions and a marked decrease in skin inflammation. The remission ofacne symptoms is significantly better than with equivalent treatmentsusing compositions which do not contain the sugar ester. Treatment iscontinued ad libitum and the skin remains substantially free from acnelesions and inflammation of the sebaceous glands. Surprisingly, adecreased number of "blackheads" is also noted.

In the above composition, the tetracycline hydrochloride is replaced byan equivalent amount of an equilibrium mixture of tetracyclinehydrochloride and epi-tetracycline hydrochloride formed by dissolvingtetracycline hydrochloride in water and allowing the solution to standat about 90° F. for about 28 days (equilibrium mix: ca. 40-45%tetracycline hydrochloride, 55-60% epi-tetracycline hydrochloride).Equivalent skin penetration enhancement and anti-acne benefits aresecured.

The composition of Example IV is modified by the addition of 0.1% byweight of sodium bisulfite and the color stability on prolonged storageis substantially increased.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of octyl methyl sulfoxide, nonyl methyl sulfoxide,undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxyundecyl methyl sulfoxide, and2-hydroxydodecyl methyl sulfoxide, respectively, and equivalent resultsare secured.

In the above composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monooctanoate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosemonodecanoate, sucrose dioleate, sucrose di-polyoxypropylene (10),glucose, dioleate polyoxyethylene (20) and sucrose palmitatepolyoxyethylene (20), respectively, and equivalent results are secured.

In the above composition the ethanol-water mixture is replaced by anequivalent amount of ethanol, 95% ethanol-5% water, isopropanol, 1:1isopropanol-water and 1:1 hexanol-water mixtures, respectively, andequivalent results are secured.

EXAMPLE V

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    0.25                                                    Colistin              0.25                                                    Decyl methyl sulfoxide                                                                              0.25                                                    Ethanol               15.0                                                    Lanolin               25                                                      Water                 Balance                                                 ______________________________________                                    

The above composition is applied to animal skin and results in asubstantial increase in the depth of penetration of the colistin intothe skin over similar compositions without the sucrose monooleate.

The above composition is useful for the treatment of first and seconddegree burns, inasmuch as the lanolin provides a soothing emollienteffect while the colistin penetrates into the burn area to combatbacterial infection.

In the above composition, the colistin is replaced by an equivalentamount of penicillin, tetracycline, tetracycline hydrochloride, anequilibrium mixture of tetracycline hydrochloride and epi-tetracyclinehydrochloride, 3,5,4'-tribromosalicyanilide,bis-(3,5,6-trichloro-2-hydroxyphenyl)methane,bis-(3,5-dichloro-2-hydroxyphenyl)sulfide,3-trifluoromethyl-4,4'-dichlorocarbanilide, 1,1'-hexamethylenebis[5'-(p-chlorophenyl)]biguanide, 1,1'-hexamethylenebis[5'-(2-ethylhexyl)]biguanide, cetylpyridinium chloride, zincundecylenate, oxytetracycline, terramycin, gramicidin, aureomycin,neomycin, tyrothricin, sulfonilamide, and zinc pyridinethione-1-oxide,respectively, and equivalent results are secured.

The above composition is formulated with the addition of 0.75% by weightof benzocaine. The penetration of the benzocaine into the burn area ispromoted by the base composition and provides a soothing anestheticbenefit to the user.

The foregoing composition is formulated using an equivalent amount ofoctyl dimethyl phosphine oxide, nonyl dimethyl phosphine oxide, decyldimethyl phosphine oxide, undecyl dimethyl phosphine oxide, dodecyldimethyl phosphine oxide, 2-hydroxydecyl dimethyl phosphine oxide,2-hydroxyundecyl dimethyl phosphine oxide, and 2-hydroxydodecyl dimethylphosphine oxide, respectively, in place of the decyl methyl sulfoxideand equivalent results are secured.

The sucrose monooleate is replaced by an equivalent amount of sucrosedioleate, sucrose dipalmitate, glucose monooctanoate, galactosemono-eicosanate, xylose, dioleate, sucrose mono-eicosanate, sucrosedi-eicosanate, maltose monopalmitate, cellibiose distearate, galactosetripalmitate, raffinose monocaprate, gentianose tri-eicosanate, andgentianose trioleate, respectively, and equivalent results are secured.

Preferred antimicrobial compositions prepared in accordance with thisinvention comprise:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 8% by weight of decyl methyl sulfoxide;

(3) from about 30% to about 70% by weight of water;

(4) from about 30% to about 70% by weight of ethyl alcohol; and

(5) from about 0.1% to about 1.0% by weight of a member selected fromthe group consisting of tetracycline hydrochloride and an equilibriummixture of tetracycline hydrochloride and epi-tetracyclinehydrochloride.

The following examples are intended to illustrate the tissue penetrationenhancing compositions of this invention containing as thepharmacologically active component from about 0.1% to about 15% byweight of a topical anesthetic agent.

EXAMPLE VI

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    0.15                                                    Decyl methyl sulfoxide                                                                              0.15                                                    Benzocaine            1.0                                                     Ethanol (95%)         50                                                      1:1 mixture of dichlorodi-                                                                          Balance                                                 fluoromethane and chloro-                                                     trifluoromethane                                                              (propellant)                                                                  ______________________________________                                    

The above composition is prepared in a pressurized can and is sprayedonto skin to provide a local anesthetic effect. The penetration of thebenzocaine into and through the skin and dermal tissue is significantlyenhanced by use of the sucrose monooleate-decyl methyl sulfoxidecomposition over compositions containing the decyl methyl sulfoxide orsucrose monooleate, alone. The enhanced penetration accounts for theimproved anesthetic affect noted.

In the above composition, the benzocaine is replaced by an equivalentamount of procaine hydrochloride, nupercaine and pontocaine,respectively, and equivalent results are secured.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of octyl methyl sulfoxide, nonyl methyl sulfoxide,undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxyundecyl methyl sulfoxide, 2-hydroxydodecylmethyl sulfoxide, octyl dimethyl phosphine oxide, nonyl dimethylphosphine oxide, decyl dimethyl phosphine oxide, undecyl dimethylphosphine oxide, dodecyl dimethyl phosphine oxide, 2-hydroxydecyldimethyl phosphine oxide, 2-hydroxyundecyl dimethyl phosphine oxide, and2-hydroxydodecyl dimethyl phosphine oxide, respectively, and equivalentresults are secured.

In the foregoing composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monooctanoate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosedipalmitate, and sucrose dioleate, respectively, and equivalent resultsare secured.

Preferred anesthetic compositions herein comprise:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 10% by weight of decyl methyl sulfoxide;

(3) from about 30% to about 70% by weight of water;

(4) from about 30% to about 70% by weight of ethyl alcohol; and

(5) from about 0.1% to about 5% by weight of a member selected from thegroup consisting of benzocaine, procaine hydrochloride, nupercaine andpontocaine.

The following examples are intended to illustrate the tissue penetrationenhancing compositions of this invention containing as thepharmacologically active agent from about 0.1% to about 20% by weight ofvarious organic sunscreens (i.e., agents which absorb ultravioletlight).

EXAMPLE VII

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    1.0                                                     Decyl methyl sulfoxide                                                                              1.0                                                     p-Aminobenzoic acid   5.0                                                     Dimethylsilicone fluid                                                                              5.0                                                     (mol. wt. 2500)                                                               Ethanol (95%)         Balance                                                 ______________________________________                                    

The above composition is prepared by simple blending and is applied toskin to provide a sunscreen effect. The penetration of thep-aminobenzoic acid into the skin is significantly enhanced by use ofthe sucrose monooleate-decyl methyl sulfoxide composition overcompositions containing the decyl methyl sulfoxide or sucrose monooleatealone. The enhanced penetration provides increased sunscreening benefitsinasmuch as the p-aminobenzoic acid is not readily removed by moistureor perspiration.

In the above composition, the p-aminobenzoic acid is replaced by anequivalent amount of homomenthyl salicylate, isopropyl cinnamate,p-methoxycinnamic acid, 2-ethylhexyl salicylate, dipropyleneglycolsalicylate, monoglyceryl, p-aminobenzoate, digalloyl trioleate, menthylanthranilate, and mixtures thereof, and equivalent results are secured.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of octyl methyl sulfoxide, nonyl methyl sulfoxide,undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxyundecyl methyl sulfoxide, 2-hydroxydodecylmethyl sulfoxide, octyl dimethyl phosphine oxide, nonyl dimethylphosphine oxide, decyl dimethyl phosphine oxide, undecyl dimethylphosphine oxide, dodecyl dimethyl phosphine oxide, 2-hydroxydecyldimethyl phosphine oxide, 2-hydroxyundecyl dimethyl phosphine oxide, and2-hydroxydodecyl dimethyl phosphine oxide, respectively, and equivalentresults are secured.

In the foregoing composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monooctanoate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosedipalmitate, and sucrose dioleate, respectively, and equivalent resultsare secured.

Preferred sunscreen compositions herein comprise:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 10% by weight of decyl methyl sulfoxide;

(3) from about 30% to about 70% by weight of water;

(4) from about 30% to about 70% by weight of ethyl alcohol; and

(5) from about 0.5% to about 10% by weight of a member selected from thegroup consisting of p-aminobenzoic acid, homomenthyl salicylate,isopropyl cinnamate, p-methoxycinnamic acid, 2-ethylhexyl salicylate,di-propyleneglycol salicylate, monoglyceryl p-aminobenzoate,digalloyltrioleate and menthyl anthranilate.

The following examples are intended to illustrate the tissue penetrationenhancing compositions of this invention containing from about 0.025% toabout 2.5% by weight of various steroids as the pharmacologically activeagent, said compositions being suitable for use as anti-inflammatories.The relative amounts of the steroid or steroid derivative used isdetermined on the basis of the relative physiological activities ofthese materials.

EXAMPLE VIII

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    0.5                                                     Decyl methyl sulfoxide                                                                               0.25                                                   Triaminolone acetonide                                                                              0.1                                                     Ethanol-water (30:70 wt.)                                                                           Balance                                                 ______________________________________                                    

The above composition is prepared as a fluid cream and is applied toskin to provide a local anti-inflammatory effect. The penetration of thetriamcinolone acetonide into and through the skin and dermal tissue issignificantly enhanced by use of the sucrose monooleate-decyl methylsulfoxide composition over compositions containing the decyl methylsulfoxide or sucrose monooleate alone. The enhanced penetration accountsfor the improved anti-inflammatory effect noted.

In the above composition, the triamcinolone acetonide is replaced by anequivalent amount of triamcinolone, fluocinolone acetonide, fluocinoloneacetonide acetate, betamethasone 17-valerate, and by 2.5% by weightconcentrations of cortisone and hydrocortisone acetate, respectively,and equivalent results are secured.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of octyl methyl sulfoxide, nonyl methyl sulfoxide,undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxyundecyl methyl sulfoxide, 2-hydroxydodecylmethyl sulfoxide, octyl dimethyl phosphine oxide, nonyl dimethylphosphine oxide, decyl dimethyl phosphine oxide, undecyl dimethylphosphine oxide, dodecyl dimethylphosphine oxide, 2-hydroxydecyldimethyl phosphine oxide, 2-hydroxyundecyl dimethyl phosphine oxide, and2-hydroxydodecyl dimethyl phosphine oxide, respectively, and equivalentresults are secured.

In the foregoing composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monooctanoate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosedipalmitate, sucrose dioleate and sorbitan monooleate polyoxyethylene(20), respectively, and equivalent results are secured.

Preferred steroid-containing compositions herein comprise:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 10% by weight of decyl methyl sulfoxide;

(3) from about 30% to about 70% of water; and

(4) from about 30% to about 70% by weight of ethyl alcohol; and (5) fromabout 0.05% to about 2.5% by weight of a steroid selected from the groupconsisting of triamcinolone acetonide, hydrocortisone acetate,triamcinolone, cortisone, fluocinolone acetonide, fluocinolone acetonideacetate and betamethansone 17-valerate.

The foregoing steroid-containing compositions are additionally suitedfor the alleviation of psoriasis, eczema and eczema-like skin disorders.

The following examples describe the tissue penetration enhancingcompositions herein and their use in conjunction with from about 0.5% toabout 15% by weight of various astringent metal salts asantiperspirants.

EXAMPLE IX

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    0.1                                                     Decyl methyl sulfoxide                                                                              2.0                                                     Aluminum chlorhydrate 5.0                                                     Ethanol (95%)         40                                                      1:1 mixture of dichloro-                                                                            Balance                                                 difluoromethane and                                                           chlorotrifluoromethane                                                        (propellant)                                                                  ______________________________________                                    

The above composition is prepared in a pressurized can and is sprayedonto skin to provide a local antiperspirant effect. The penetration ofthe aluminum chlorhydrate into and through the skin and dermal tissue issignificantly enhanced by e of the sucrose monooleatedecyl methylsulfoxide compositions over compositions containing the decyl methylsulfoxide or sucrose monooleate alone. The antiperspirant effectivenessof the compositions is assessed using the "forearm test" fully describedin U.S. Pat. No. 3,527,864, above. The enhanced penetration accounts forthe improved anti-perspirant effect noted.

In the above composition, the aluminum chlorhydrate is replaced by anequivalent amount of zirconium oxychloride, zinc chloride, aluminumtribromide, aluminum chloride ethanolate, and a 1:1 weight mixture ofzirconium oxychloride and aluminum chlorhydrate, respectively, andequivalent results are secured.

In the above composition, the decyl methyl sulfoxide, is replaced by anequivalent amount of octyl methyl sulfoxide, nonyl methyl sulfoxide,undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxyundecylmethyl sulfoxide, 2-hydroxydodecylmethyl sulfoxide, octyl dimethyl phosphine oxide, nonyl dimethylphosphine oxide, decyl dimethyl phosphine oxide, undecyl dimethylphosphine oxide, dodecyl dimethyl phosphine oxide, 2-hydroxydecyldimethyl phosphine oxide, 2-hydroxyundecyl dimethyl phosphine oxide, and2-hydroxydodecyl dimethyl phosphine oxide, respectively, and equivalentresults are secured.

In the foregoing composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monooctanoate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosedipalmitate, and sucrose dioleate, respectively, and equivalent resultsare secured.

Preferred antiperspirant compositions herein comprise:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 10% by weight of decyl methyl sulfoxide;

(3) from about 50% to about 90% by weight of ethyl alcohol; and

(4) from about 1% to about 10% by weight of an astringent metal saltselected from the group consisting of aluminum chlorhydrate, zirconiumoxychloride and mixtures thereof.

The following examples describe compositions comprising the sugar ester,skin penetration enhancing agent and, as the pharmacologically activeagent, various antimetabolites useful in the treatment of psoriasis.

EXAMPLE X

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    1.0                                                     Decyl methyl sulfoxide                                                                              1.0                                                     Methotrexate          2.0                                                     Ethanol               25.0                                                    Water                 Balance                                                 ______________________________________                                    

The above composition is admixed by simple blending and is applied toskin. The penetration of the Methotrexate into and through the skin anddermal tissue is significantly enhanced by use of the sucrosemonooleate-decyl methyl sulfoxide composition over compositionscontaining the decylmethyl sulfoxide or sucrose monooleate alone. Theenhanced penetration provides improved anti-psoriasis benefits.

In the above compositions the Methotrexate is replaced by an equivalentamount of 5-methyldeoxycytidine, puromycin, arabinosyl cytosine,hydroxyurea and theophylline, respectively, with equivalent results.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of octyl methyl sulfoxide, nonyl methyl sulfoxide,undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxyundecyl methyl sulfoxide, 2-hydroxyundecylmethyl sulfoxide, octyl dimethyl phosphine oxide, nonyl dimethylphosphine oxide, decyl dimethyl phosphine oxide, undecyl dimethylphosphine oxide, dodecyl dimethyl phosphine oxide, 2-hydroxydecyldimethyl phosphine oxide, 2-hydroxyundecyl dimethyl phosphine oxide, and2-hydroxydodecyl dimethyl phosphine oxide, respectively, and equivalentresults are secured.

In the foregoing composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monooctanoate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosedipalmitate, and sucrose dioleate, respectively, and equivalent resultsare secured.

Preferred antimetabolite compositions herein comprise:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 10% by weight of decyl methyl sulfoxide;

(3) from about 30% to about 70% by weight of water;

(4) from about 30% to about 70% by weight of ethyl alcohol; and

(5) from about 0.1% to about 10% by weight of a member selected from thegroup consisting of Methotrexate, 5-methyldeoxycytidine, puromycin,arabinosyl cytosine, and hydroxyurea.

The following examples describe compositions comprising the sugar ester,skin penetration enhancing agent and, as the pharmacologically activeagent, from about 0.1% to about 10% by weight of Vitamin A or commercialpreparations containing at least about 10,000 units of Vitamin Aactivity per gram.

EXAMPLE XI

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    1.0                                                     Decyl methyl sulfoxide                                                                              1.0                                                     Vitamin A             1.0                                                     Sorbitan Monooleate Poly-                                                     oxyethylene (Emulsifier)                                                                            2.0                                                     Lanolin               5.0                                                     Water                 Balance                                                 ______________________________________                                    

The above composition is applied to skin to provide anti-acne benefits.The penetration of the Vitamin A into and through the skin and dermaltissue is significantly enhanced by use of the sucrose monooleate-decylmethyl sulfoxide composition over compositions containing the decylmethyl sulfoxide or sucrose monooleate alone.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of octyl methyl sulfoxide, nonyl methyl sulfoxide,undecyl methyl sulfoxide, dodecyl methyl sulfoxide, 2-hydroxydecylmethyl sulfoxide, 2-hydroxyundecyl methyl sulfoxide, 2-hydroxydodecylmethyl sulfoxide, octyl dimethyl phosphine oxide, nonyl dimethylphosphine oxide, decyl dimethyl phosphine oxide, undecyl dimethylphosphine oxide, dodecyl dimethyl phosphine oxide. 2-hydroxydecyldimethyl phosphine oxide, 2-hydroxyundecyl dimethyl phosphine oxide, and2-hydroxydodecyl dimethyl phosphine oxide, respectively, and equivalentresults are secured.

In the foregoing composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monooctanoate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosedipalmitate, and sucrose dioleate, respectively, and equivalent resultsare secured.

Preferred vitamin compositions herein comprise:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 10% by weight of decyl methyl sulfoxide;

(3) from about 30% to about 70% by weight of water;

(4) from about 30% to about 70% by weight of ethyl alcohol; and

(5) from about 0.1% to about 2% by weight of Vitamin A.

The following examples describe compositions comprising the sugar ester,skin penetration enhancing agent and, as the pharmacologically activeagent, from about 0.1% to about 10% by weight of various natural oilswellknown for their rubifacient and analgesic activity and ability toaid in the relief of muscular strain.

EXAMPLE XII

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    1.0                                                     Decyl methyl sulfoxide                                                                              1.0                                                     Oil of Wintergreen    2.0                                                     Hexanol               Balance                                                 ______________________________________                                    

The above composition is prepared by blending and is applied to skin toalleviate the discomforts of simple muscular strain. The penetration ofthe oil of wintergreen into and through the skin and muscular tissue issignificantly enhanced by use of the sucrose monooleatedecyl methylsulfoxide composition over compositions containing the decyl methylsulfoxide or sucrose monooleate alone.

In the above composition, the oil of wintergreen is replaced by anequivalent amount of tincture of camphor, clove oil, and mixturesthereof, respectively, and equivalent results are secured.

The composition is formulated with the addition of about 0.01% by weightof cantharidin and provides an effective medication for treating mangein dogs and cattle.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of 2-ketooctyl methyl sulfoxide, 3-methoxyundecylmethyl sulfoxide, 3,6-dioxadodecyl methyl sulfoxide, 3-octenylhydroxymethyl sulfoxide, 2-hydroxyoctyl methyl sulfoxide,bis-(2-hydroxyoctyl)sulfoxide, 2-hydroxydodecyl hydroxymethyl sulfoxide,trimethyl phosphine oxide, phenyl dimethyl phosphine oxide, naphthylethyl hydroxymethyl phosphine oxide, 2-propenyl diethyl phosphine oxide,2-ketobutyl diethanol phosphine oxide, 2-methoxybutyl methyl ethylphosphine oxide, 2-chlorodecyl dimethyl phosphine oxide, 2-oxaheptyldimethyl phosphine oxide, 3-azahexyl dimethyl phosphine oxide, phenyldimethyl phosphine oxide and methyl dibenzyl phosphine oxide,respectively, and equivalent results are secured.

In the foregoing composition, the sucrose monooleate is replaced by anequivalent amount of sucrose monooctanoate, sucrose monolaurate, sucrosemonomyristate, sucrose monopalmitate, sucrose monostearate, sucrosedipalmitate, and sucrose dioleate, respectively, and equivalent resultsare secured.

Preferred rubifacient compositions herein comprise:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 10% by weight of decyl methyl sulfoxide;

(3) from about 30% to about 70% by weight of water;

(4) from about 30% to about 70% by weight of ethyl alcohol; and

(5) from about 0.1% to about 5% by weight of a member selected from thegroup consisting of oil of wintergreen, tincture of camphor, andmixtures thereof.

From the foregoing it is seen that the compositions herein enhance thepenetration of a wide variety of pharmacologically active chemicalsubstances into and through animal tissue. Furthermore, it is recognizedthat the compositions herein containing the various pharmacologicallyactive agents are especially adapted to treatment of various diseaseconditions in humans and in animals by topical application thereto. Theproportions of pharmacologically active agents disclosed in the examplesare merely for the purposes of illustration inasmuch as theseproportions can be varied depending on the type of agent being used, therelative severity of the disease condition, the rate of application bythe user and the like.

It is further recognized that combinations of one, or more,pharmacological agents can be used conjointly with thepenetration-enhancing compositions herein. For example, the conjoint useof steroidal anti-inflammatory materials with antimicrobial andanti-fungal agents is an art-recognized method for obtaining an improvedanti-inflammatory response with inflamed tissue. The following exampleillustrates such a composition comprising asteroid-antimicrobial-antifungal composition in combination with thepenetration-enhancing base of this invention.

EXAMPLE XIII

    ______________________________________                                                              Percent                                                 Ingredient            (By Weight)                                             ______________________________________                                        Sucrose monooleate    1.0                                                     Decyl methyl sulfoxide                                                                              0.15                                                    Triamcinolone acetonide                                                                             0.05                                                    Neomycin sulfate      0.20                                                    Gramicidin            0.05                                                    Ethanol-water (1:1)   Balance                                                 ______________________________________                                    

The above composition is prepared by blending the respective ingredientsand is applied to skin to alleviate inflammation and the symptoms ofeczema. The penetration of the triamcinolone acetonide, neomycin sulfateand gramicidin into the skin is significantly enhanced by the use of thesucrose monooleate-decyl methyl sulfoxide composition over compositionscontaining the decyl methyl sulfoxide or sucrose monooleate, alone.

In the above composition, the gramicidin is replaced by an equivalentamount of bacitracin and equivalent results are secured.

In the above composition, the decyl methyl sulfoxide is replaced by anequivalent amount of 3-octenyl methyl sulfoxide, 2-hydroxydecyl2-hydroxyethyl sulfoxide, 2-hydroxydecyl bis-(hydroxymethyl)phosphineoxide, and tris-(hydroxymethyl)phosphine oxide, respectively, andequivalent results are secured.

In the above composition, the sucrose monooleate is replaced by anequivalent amount of fructose monopalmitate polyoxyethylene (20),galactose tri-polyoxybutylene (50) and sucrose di-polyoxypropylene (20),respectively, and equivalent results are secured.

It is also recognized that the invention encompasses as a method aspecta process for enhancing the penetration of pharmacologically activeagents into and through animal tissue, especially skin, comprisingapplying said pharmacologically active agent topically to said tissue incombination with a sugar ester and a sulfoxide or phosphine oxide of thetype disclosed herein. Sucrose monooleate and decyl methyl sulfoxide atproportions of sulfoxide: sucrose monooleat:pharmacologically activeagent of from about 1:1:1 to about 1:1:10 are preferred in suchprocesses. Tetracycline hydrochloride and equilibrium mixtures oftetracycline hydrochloride and epi-tetracycline hydrochloride applied inthis manner are especially efficacious in the treatment of acne.

Because of storage stability considerations relating to tetracyclinehydrochloride and epi-tetracycline hydrochloride when formulated insolution, it is preferred herein to package anti-acne compositionsprepared in the manner of this invention in kit form. That is to say, itis preferred hereinn to package the mixture of epi-tetracyclinehydrochloride and tetracycline hydrochloride separately from the mixtureof ethyl alcohol, water, sucrose monooleate and decyl methyl sulfoxide.Similar considerations also obtain when dealing with the other sugaresters, alcohols, and penetration enhancing agents disclosed hereinemployed in combination with tetracycline hydrochloride andepi-tetracycline hydrochloride. Accordingly, a preferred embodiment ofthe present invention encompasses a separately packaged portion of anequilibrium mixture of tetracycline hydrochloride and epitetracyclinehydrochloride as disclosed hereinabove, and a separately packagedportion of the penetration enhancing carrier of the present invention.Such separately packaged portions are stable on prolonged storage andcan be admixed by the user immediately before the course of treatment.It is convenient to package sufficient quantities of the two portions toprovide a sufficient quantity of the anti-acne composition to last forabout 4 to about 8 weeks of treatment. This, of course, is not criticalto the present invention inasmuch as the clinical efficacy of thecompositions herein is satisfactory even after storage. However, the useof separate packages for the tetracycline hydrochloride plusepi-tetracycline hydrochloride equilibrium mixture and for the fluidointment base insures that fresh material will be provided to the user.

The size of the kits herein is of no consequence to the practice of theinvention. For example, such kits can be provided which contain only afew grams of material and which are suitable for but a singleapplication. Alternatively, kits can be provided which comprise arelatively large volume of the penetration enhancing base and multiplepackets of the mixture of tetracycline hydrochloride andepi-tetracycline hydrochloride. The user can then measure aliquots ofthe base and add thereto a premeasured packet of the antibiotic mixture.It is preferred herein to provide an anti-acne composition in kit formcomprising a separately packaged, fluid ointment base comprising fromabout 0.1% to about 1% by weight of sucrose monooleate, from about 0.1%to about 8% by weight of decyl methyl sulfoxide, from about 30% to about70% by weight of water, and from about 30% to about 70% by weight ofethyl alcohol. The second component of the kit comprises a separatelypackaged, dry portion of an anti-acne agent comprising an equilibriummixture of tetracycline hydrochloride and epi-tetracycline hydrochloridein an amount sufficient to provide a 0.1% to 1.0% (wt.) concentration ofsaid equilibrium mixture when dissolved in said fluid ointment basecomposition. Preferably, the equilibrium mixture of tetracyclinehydrochloride and epi-tetracycline hydrochloride contains from about0.05% to about 0.15% by weight (based on the total weight of allcomponents) of a color stabilizer, especially sodium bisulfite.Alternatively, the second component can be an equivalent amount ofeither tetracycline hydrochloride or epi-tetracycline hydrochloride,since these materials are stable in the dry state. The following exampleillustrates such an anti-acne kit.

EXAMPLE XIV

    ______________________________________                                        Component 1                                                                   Ingredient              Wt.                                                   ______________________________________                                        Tetracycline hydrochloride,                                                                           0.06 oz.                                              epi-tetracycline hydrochloride                                                equilibrium mixture                                                           Sodium bisulfate        0.02 oz.                                              Component 2                                                                   Ethyl alcohol            4 oz.                                                Sucrose monooleate      0.06 oz.                                              Decyl methyl sulfoxide  0.06 oz.                                              Water                   2.5 oz.                                               ______________________________________                                    

In the composition of Example XIV, Component 1 is packaged in a dry,waterproof, foil packet; Component 2 is packaged in a bottle havingsufficient headspace to allow mixing. Immediately prior to use,Component 1 is added to Component 2 and the mixture is shaken to mix.The user applies an effective amount of the composition to the acnelesion, ad lib, and alleviation of the acne is secured.

In the above composition, the mixture of tetracycline hydrochloride andepi-tetracycline hydrochloride is replaced by tetracycline hydrochlorideand epi-tetracycline hydrochloride, respectively, and equivalent resultsare secured.

The preferred acne treatment of this invention comprises applying aneffective amount of the composition of Examples IV or XIV to afflictedskin. Of course, it is preferred to cleanse the skin prior to treatment,and any soap or detergent composition suitable for washing the skin canbe employed. However, it has surprisingly been discovered that, of themany detergents extant, sodium alkyl benzene sulfonate (avg. C₁₂ linearalkyl chain; commercial material) appears to enhance the anti-acneefficacy of the compositions herein. That is to say, acne lesionscleansed with an effective amount of an aqueous solution of sodium alkylbenzene sulfonate immediately prior to application of the anti-acnecompositions herein are reduced in size and severity more rapidly thanwhen the anti-acne composition is applied without pre-cleansing, or whensuch pre-cleansing is carried out with soaps or synthetic surfactantsother than the sodium alkyl benzene sulfonate.

In a method aspect of this invention, acne lesions are treated byapplying thereto an effective amount of an anti-acne compositioncomprising:

(1) from about 0.1% to about 1% by weight of sucrose monooleate;

(2) from about 0.1% to about 8% by weight of decyl methyl sulfoxide;

(3) from about 30% to about 70% by weight of water;

(4) from about 30% to about 70% by weight of ethyl alcohol; and

(5) from about 0.1% to about 1.0% by weight of a member selected fromthe group consisting of tetracycline hydrochloride, epi-tetracyclinehydrochloride, and an equilibrium mixture of tetracycline hydrochlorideand epi-tetracycline hydrochloride.

In a preferred method aspect, the acne lesions are first cleansed withan effective amount of an aqueous solution of sodium alkyl benzenesulfonate prior to application of an effective amount of the aforesaidanti-acne composition.

What is claimed is:
 1. A composition for enhancing the penetration ofpharmacologically active agents into and through animal tissuecomprising:(1) at least about 0.1% by weight of a sugar ester selectedfrom the group consisting ofsucrose monooctanoate, sucose monodecanoate,sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate,sucrose monostearate, sucrose monooleate, and sucrose dioleate; and (2)at least about 0.1% by weight of a phosphine oxide compound selectedfrom the group consisting ofoctyl dimethyl phosphine oxide, nonyldimethyl phosphine oxide, decyl dimethyl phosphine oxide, undecyldimethyl phosphine oxide, dodecyl dimethyl phosphine oxide,2-hydroxydecyl dimethyl phosphine oxide, 2-hydroxyundecyl dimethylphosphine oxide, and 2-hydroxydodecyl dimethyl phosphine oxide.